Molecular oxygen is an essential nutrient for nonfacultative aerobic organisms, including humans. Oxygen, although essential for aerobic metabolism, can be converted to poisonous metabolites, such as superoxide anion and hydrogen peroxide, collectively known as reactive oxygen species. Excessive concentrations of various forms of oxygen and of free radicals can have serious adverse effects on living systems, including the peroxidation of membrane lipids, the hydroxylation of nucleic acid bases, and the oxidation of sulfhydryl groups and other sensitive moieties in proteins. If uncontrolled, mutations and cell death result.
Biological antioxidants include well-defined naturally occurring metalloenzymes, such as superoxide dismutase (SOD), catalase (CAT), and selenium glutathione peroxidase, as well as the enzyme, phospholipid hydroperoxide glutathione peroxidase. A large number of diseases or degenerative processes are related to disorders with metalloenzymes involved in the detoxification of reactive oxygen species derived from dioxygen reduction. The role of these metalloenzymes has been demonstrated with animals under-expressing SOD or CAT enzymes. In addition, the induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase has recently been shown (Estxc3xa9vez et al. (2000), Science, 286:2498-2500).
Obstacles exist for the use of recombinant metalloenzymes in therapy including: solution instability, limited cellular accessibility, immunogenicity, short half-lives, cost of production and proteolytic digestion. These synthetic catalytic scavengers must be stable in physiological conditions and, in particular, the metal should be strictly inserted within the ligand to avoid any demetallation and trapping of the metal ion by serum proteins. These synthetic catalytic scavengers must also be soluble in water at pH 7.0. Avoiding synthetic molecules that lead to DNA cleavage is an additional concern.
Consequently, there is a need for new synthetic transition metal complexes with the ability to catalyze the dismutation of the reactive oxygen species derived from the non-controlled reduction of dioxygen. The need exists for providing non-genotoxic water soluble metallophorphyrin derivatives able to act as SOD and CAT mimics without creating oxidative damage of DNA.
The present invention relates to compounds which are effective as synthetic catalytic scavengers for reactive oxygen species. The compounds are effective as superoxide dismutase (SOD), and/or catalase (CAT), and/or peroxidase (POD) mimetics which, accordingly, have antioxidant and/or free radical scavenging properties and function in vivo as antioxidants. In particular, the present invention relates to non-genotoxic metalloenzyme mimetics, pharmaceutical formulations containing them, methods for their preparation and the use of such compounds in prophylaxis and therapy for diseases and degenerative processes resulting from reactive oxygen species.
The metallophorphyrin derivatives of this invention can be represented by Structural Formula I: 
In a preferred embodiment, Structural Formula I is a complex containing a metal ion, preferably a transition metal such as manganese or iron. In Structural Formula I, R1, R2, R3 and R4 are the same or different and are each a group of the formula: 
where L is a linker of about 2 to about 12 atoms in length. The atoms within the linker are carbon atoms optionally interspersed with from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. Preferably L is a linear C2-C6 alkylene group, more preferably ethylene, X is nitrogen or phosphorus; R13, R14 and R15 are each, independently, hydrogen, alkyl or arylalkyl; Y- is a monovalent anion; R5, R6, R7, R8, R9, R10, R11 and R12 are each independently selected from the group consisting of hydrogen, alkyl and halo; and each R16 independently represents one or more substituents independently selected from the group consisting of hydrogen, hydroxy, halo and alkyl.
Herein, halo is, for example, fluoro, chloro, bromo, iodo; preferably it is fluoro, chloro or bromo.
The counter monovalent anion Y can represent any suitable anion with which the complex of Structural Formula I can be formed. Suitable examples include chloride, hydroxide and acetate, preferably chloride or acetate.
In another embodiment, the invention relates to methods of preparing compounds of Structural Formula I.
In another aspect, the invention provides methods of using the compounds of Structural Formula I for prophylaxis or treatment of a free radical associated disease or condition in a mammal.
In yet another aspect, the invention provides pharmaceutical formulations comprising one or more pharmaceutically acceptable carriers, diluents or excipients and a therapeutically effective amount of compound represented by Structural Formula I.
In yet another embodiment, the invention relates to methods of treating, preventing or arresting free radical associated diseases or conditions comprising administering to an individual in need thereof a therapeutically effective amount of a compound represented by Structural Formula I.